tbuckley/cabot-search huggingface dataset:
Abstract 3432: A novel anti-CLDN6-CD137 bispecific antibody (NBL-028) for treating Claudin 6 positive solid tumors
Authors: Raymond Yu, Yong Tong, Huarui Lu, Makenzie Danton, Samantha Dillman, Joshua Dewe, Joshua Karchin, Samruddhi Patil, Danielle Lavery, Haichun Huang, James Pei, Zhong Liu, Han Li, Ming Lei
Journal: Cancer Research (2022)

Abstract Claudin-6 is a tetraspan membrane protein associated with tight junction formation. Its expression in normal tissues is restricted to the fetal organs but is not detected in the adult tissues. Increased expression of CLDN6 has been shown in several human malignancies such as testicular, ovarian, uterine, liver and lung adenocarcinoma, and is associated with poor prognosis in these cancer patients. Therefore, CLDN6 is a promising tumor-associated antigen (TAA) for tumor-targeting therapeutics such as CART and T cell engaging bispecific antibodies. CD137 co-stimulation has been reported to lead to extended T-cell proliferation, reactivating anergic T cells, promoting memory T cell formation and maintenance. Activating CD137 with agonistic antibodies presents a great opportunity to improve the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or overcome resistance to ICIs. Additionally, a bispecific antibody that activates CD137 signaling only in the presence of TAA would help reduce the dose-dependent hepatotoxicity that was observed in clinical trials with monoclonal anti-CD137 agonistic antibody due to the activation of CD137 signaling in liver resident Kupffer cells. NBL-028 is a novel tetravalent bispecific antibody uniquely designed to activate the CD137 co-stimulatory pathway in the tumor microenvironment through the CLDN6-mediated clustering of CD137. NBL-028 binds to Claudin 6 with high affinity and specificity, activates CD137 in a CLDN6-dependent manner with fast-on and fast-off CD137 binding properties. NBL-028 demonstrated strong CLDN6-dependent T-cell activation and T-cell mediated cytotoxicity in vitro. NBL-028 elicits potent anti-tumor effects and immunological memory in mouse models without detectable liver damages or systemic toxicity. The tumor infiltrated Lymphocyte (TIL) analysis also demonstrated that NBL-028 treatment induced CD45+ immune cells infiltration, decreased Treg/CD8 ratio and increased M1/M2 like macrophage ratio. Furthermore, NBL-028 is designed upon a proprietary molecular scaffold with superior developability features, demonstrated by stability, yield and ease to purify. NBL-028 is currently at the stage of IND-enabling activities with the aim to enter clinical studies for treating Claudin 6 positive solid tumors in 1Q 2023. Citation Format: Raymond Yu, Yong Tong, Huarui Lu, Makenzie Danton, Samantha Dillman, Joshua Dewe, Joshua Karchin, Samruddhi Patil, Danielle Lavery, Haichun Huang, James Pei, Zhong Liu, Han Li, Ming Lei. A novel anti-CLDN6-CD137 bispecific antibody (NBL-028) for treating Claudin 6 positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3432.
Abstract 5402: Urothelial carcinomas in different anatomical positions exhibit distinct genomic and immunological characteristics
Authors: Ruiqian Li, Hushan Zhang, Qilin Wang, Hong Yang, Yu Bai, Chen Hu, Hongyi Wu, Chongjian Zhang, Ziyong Wang, Qiwei Wang, Pengjie Xu, Jun Li
Journal: Cancer Research (2022)

Abstract Background Human bladder cancers were recently suggested to be grouped into different molecular subtypes. However, little is known about the difference in gene landscape between upper tract urothelial carcinoma (UTUC) and lower tract urothelial carcinoma (LTUC) of Chinese patients. Herein, we analyzed the genomic characteristics of primary UTUC and LTUC in China. Methods The formalin-fixed paraffin-embedded specimens of 250 LTUC and 121 UTUC patients have been consecutively collected and have underwent next-generation sequencing (NGS) from 2018 to 2021 in 3DMed Clinical Laboratory Inc. Gene mutation and TMB level were analyzed by NGS, detected PD-L1 expression by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. Results NGS analysis showed that, in the samples of UTUC, the top ten gene mutations were CDKN2A/2B 6.6% (8/121), TP53 5.8% (7/121), FGF19 5.8% (7/121), TERT 3.3% (4/121), PREX2 3.3% (4/121), FRS2 3.3% (4/121), KDM6A 2.5% (3/121), PIK3CA 2.5% (3/121), EGFR 2.5% (3/121), MYCL 2.5% (3/121); while in the LTUC, the top gene mutations were TP53 44.4% (111/250), TERT 31.6% (79/250), CDKN2A/2B 25.7% (64/250), FGF3 18% (45/250), KDM6A 17.6% (44/250), PIK3CA 16.4% (41/250), RB1 14.0%(35/250), DGFR3 13.6% (34/250), ARID1A 12.4% (31/250). Furthermore, TMB level and PD-L1 expression in the UTUC and LTUC were also analyzed, and results showed that although the gene mutation was totally different, but no significant difference was found on TMB level (p&amp;gt;0.05). However, among these patients, higher PD-L1 expression level were found in UTUC than LTUC (p&amp;lt;0.05). Conclusion UTUC and LTUC in Chinese patients hold different gene landscape and PD-L1 expression, this suggested these patients may have different prognosis and response differently to targetable therapy and immunotherapy. Citation Format: Ruiqian Li, Hushan Zhang, Qilin Wang, Hong Yang, Yu Bai, Chen Hu, Hongyi Wu, Chongjian Zhang, Ziyong Wang, Qiwei Wang, Pengjie Xu, Jun Li. Urothelial carcinomas in different anatomical positions exhibit distinct genomic and immunological characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5402.
Abstract 2313: Fenbendazole induces cell cycle arrest in colorectal cancer cells and patient-derived colon cancer organoids
Authors: Kyung-Sun Kang, Da-Hyun Kim
Journal: Cancer Research (2022)

Abstract Colorectal cancer is one of leading cause of cancer-related deaths. Therefore, there have been various attempts to cure the cancer by developing new efficient anti-cancer therapy in addition to surgical resection and chemotherapy. In this study, we investigated the effects of fenbendazole, an anti-helminthic drug, both colon cancer cells and patient-derived colon tumor organoids. Notably, we employed 3D tumor organoid models because 2D-cultured cell lines were not able to recapitulate the physiology of solid tumors. We first observed that treatment of fenbendazole to colon cancer cells induced apoptosis within 24 hours, which was extended for a long-term. We revealed that fenbendazole markedly suppressed proliferation rate via cell cycle arrest. Cell cycle progression is elaborately regulated by multiple genes, such as cyclins and cyclin-dependent kinases (CDKs). From a screening of cell cycle-related factors, we found that the protein levels of CDK1 phosphorylated at Tyr15 and cyclin B1 which was known to regulate M phase transition, were drastically downregulated when the tumor cells were exposed to fenbendazole. Next, colorectal tumor-bearing mouse model was established using AOM/DSS. Oral administration of fenbendazole into the mouse not only reduced the number of tumor cells but also lowered tumor grades. Overall, our study suggested a possibility that fenbendazole could be applied for anti-cancer therapy by targeting cell cycle arrest. Citation Format: Kyung-Sun Kang, Da-Hyun Kim. Fenbendazole induces cell cycle arrest in colorectal cancer cells and patient-derived colon cancer organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2313.
Abstract 5817: Exosomal miR-4466 from nicotine-activated neutrophils promotes tumor cell stemness &amp; metabolism in brain metastasis
Authors: Abhishek Tyagi, Shih-Ying Wu, Sambad Sharma, Kerui Wu, Dan Zhao, Ravindra Deshpande, Kounosuke Watabe
Journal: Cancer Research (2022)

Abstract Smoking is associated with lung cancer and has a profound impact on tumor immunity. Nicotine, the addictive and non-carcinogenic smoke component, influences various brain cells and the immune system. However, little is known how long-term use of nicotine affects clinical outcomes in patients with brain metastasis. To address this question, we conducted a retrospective analysis of 810 lung cancer patients with smoking history and assessed brain metastasis. We found that lung cancer patients of current smokers have significantly higher brain metastatic incidence compared to the never-smokers. Immune profiling of the brain metastatic lesions among smokers showed predominant infiltration of neutrophils compared to never-smokers. Notably, mice pre-exposed to nicotine showed a significantly increased number of neutrophils in the brains even before implantation of cancer cells (pre-metastatic niche), and their numbers progressively increased during the metastatic stage. Neutrophil depletion during metastatic colonization caused a remarkable decrease in brain metastasis. Furthermore, we found that chronic exposure of nicotine recruited STAT3-activated N2-neutrophils that secreted exosomal miR-4466 in the brain. This pre-metastatic niche promoted stemness and metabolic switching via SKI/SOX2/CPT1A axis in the tumor cells thereby enabling brain metastasis. Importantly, exosomal miR-4466 levels were found to be elevated in serum/urine of cancer-free subjects with a smoking history and promote tumor growth in vivo, suggesting that exosomal miR-4466 may serve as a promising prognostic biomarker for predicting increased risk of metastatic disease among smoker(s). Our findings suggest a novel pro-metastatic role of nicotine-induced N2-neutrophils in the progression of brain metastasis. We also demonstrated that inhibiting nicotine-induced STAT3-mediated neutrophil polarization effectively abrogated brain metastasis in vivo. Our finding for the first time provides compelling evidence related to the mechanism(s) of neutrophil-mediated brain metastasis that arises from nicotine use. Our results also identified a potential prognostic biomarker for the onset of metastasis as a risk-reduction measure in lung cancer patients and implicated the risk of using nicotine gateway for smoking cessation in cancer patients with a smoking history. Citation Format: Abhishek Tyagi, Shih-Ying Wu, Sambad Sharma, Kerui Wu, Dan Zhao, Ravindra Deshpande, Kounosuke Watabe. Exosomal miR-4466 from nicotine-activated neutrophils promotes tumor cell stemness &amp; metabolism in brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5817.
Abstract 6221: Tandem use of multi-omics and artificial intelligence identified novel prognostic and therapeutic biomarkers for head and neck squamous cell carcinoma
Authors: Ajaz A. Bhat, Tariq Masoodi, Deepika Mishra, Mayank Singh, Sabah Nisar, Sheema Hashem, Sana K. Baba, Puneet Bagga, Ravinder Reddy, Davide Bedognetti, Shahab Uddin, Wael El-Rifai, Muzafar A. Macha, Mohammad Haris
Journal: Cancer Research (2022)

Abstract Introduction: Head and neck squamous cell carcinoma (HNSCC) is categorized into Human Papilloma Virus positive (HPV+ve) and negative (HPV-ve) tumors, with the latter being more aggressive and displaying poor overall survival (OS). There is a need to identify aggressive biomarkers for patient stratification and improved patient care. Materials and Methods: Using the multi-omics data, including somatic mutations, copy number alterations, RNA sequencing, miRNA sequencing, and methylation from 513 HNSCC patients, we performed an integrative clustering analysis to differentiate HPV+ve and HPV-ve tumors and identify novel prognostic biomarkers for survival and treatment response. Using artificial intelligence (AI) based machine learning approach by implementing scikit-learn, we developed a model to predict the patient's OS. Results: Our clustering analysis robustly segregated HNSCC patients into HPV+ve and HPV-ve tumors. Artificial intelligence-based machine learning model identified a 30 gene signature panel specific to HPV-ve tumors precisely predicting poor OS with an accuracy of 90.5±0.8% (95% CI) and AUC of 80.2%. Furthermore, the multivariate Cox regression survival model identified 12 genes as independent prognostic biomarkers in HPV-ve tumors, including overexpression of novel genes NT5E and TRIML2. Interestingly, higher expression of NT5E and TRIML2 due to promoter hypomethylation predicted therapy resistance in 62.8% and 65.1% of HNSCC patients, respectively. The prognostic signature panel of 30 genes was further validated using three additional expression data sets (n = 450) of HNSCC. Conclusion: Our multi-omics and AI analysis revealed a novel HPV-ve molecular cluster with implications for predicting disease aggressiveness, therapeutic response, and OS in HNSCC patients. Citation Format: Ajaz A. Bhat, Tariq Masoodi, Deepika Mishra, Mayank Singh, Sabah Nisar, Sheema Hashem, Sana K. Baba, Puneet Bagga, Ravinder Reddy, Davide Bedognetti, Shahab Uddin, Wael El-Rifai, Muzafar A. Macha, Mohammad Haris. Tandem use of multi-omics and artificial intelligence identified novel prognostic and therapeutic biomarkers for head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6221.
Abstract 2029: Multiomic analysis of whole transcriptome and high plex protein assays on a single FFPE slide
Authors: Shilah Bonnett, Nicholas Confuorto, Kit Fuhrman, Giang Ong, Alyssa Rosenbloom, John Lyssand, Gary Geiss, Joseph Beechem
Journal: Cancer Research (2022)

Abstract The GeoMx࣪ Digital Spatial Profiler (DSP) enables high-plex, high-throughput spatial profiling and quantification from a single slide for either protein or RNA. To fully understand the interplay between RNA and protein in tissue, we have developed a novel multi analyte assay that allows for the profiling of both analytes from the area of interest (AOI) on a single slide. Here we describe the development and performance of the multi analyte assay on cell pellet array (CPA) and various tissues including tonsil and colorectal cancer (CRC) using a high plex GeoMx Protein Panel and the GeoMx Human Whole Transcriptome Atlas (WTA). We successfully identified conditions to detect RNA and protein simultaneously, with comparable sensitivity and specificity to the single analyte conditions. The data accurately matched cell lines in an unbiased correlation analysis between GeoMx WTA and the entire CCLE RNAseq database. Furthermore, the assay performance was maintained in tissue samples. Tonsil and colorectal cancer biopsies were profiled for RNA (whole transcriptome) and protein from the same AOI, allowing simultaneous measurements of transcriptional and translational regulation of key biological pathways. This multi-analyte profiling enables deeper characterization of precious biological samples that are available in limited quantities. Citation Format: Shilah Bonnett, Nicholas Confuorto, Kit Fuhrman, Giang Ong, Alyssa Rosenbloom, John Lyssand, Gary Geiss, Joseph Beechem. Multiomic analysis of whole transcriptome and high plex protein assays on a single FFPE slide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2029.
Abstract 5314: Selinexor, a selective inhibitor of nuclear export (SINE) compound, enhances the anti-tumor activity of Eribulin in leiomyosarcoma
Authors: Sonam Mittal, Ishaque Pulikkal, Hua Chang, Yosef Landesman, John Charlson, Sunila Pradeep
Journal: Cancer Research (2022)

Abstract Leiomyosarcoma (LMS) is a rare soft tissue sarcoma (STS) that begins in smooth muscle tissue and most often initiates in the abdomen or uterus. Compared with other uterine cancers, uterine LMS is an aggressive tumor associated with poor prognosis and has a high risk of recurrence and death, regardless of stage at presentation. Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound that binds covalently to exportin 1, thereby reactivating tumor suppressor proteins and downregulating the expression of oncogenes and DNA damage repair (DDR) proteins. Selinexor has demonstrated preclinical activity in various cancer types, including STS, and is currently in Phase I and II clinical trials for advanced cancers (Marretta et al. 2021). In this study, we evaluated the effects of Selinexor in combination with Dacarbazine, Gemcitabine, Doxorubicin, Pazopanib, Eribulin, and Trabectedin in LMS cell lines. The effects on cell viability were evaluated by treating the LMS cell lines SK-UT1 (p53-mut) and SK-UT1-B (p53 WT) with Selinexor and different chemotherapy combinations. Treatment with these drugs significantly decreased the cell proliferation and survival of SK-UT1 and SK-UT1-B cell lines tested in vitro. However, this effect was enhanced in SK-UT1 cells following treatment in the combination of Selinexor with Eribulin and Doxorubicin. The effects of treatment were also evaluated in mouse xenograft models generated with SK-UT1 cell lines. Treatment with Selinexor combined with Eribulin showed synergistic effects on tumor growth inhibition in SK-UT1 derived xenografts which warrant further investigation of these combinations at the clinical level. Citation Format: Sonam Mittal, Ishaque Pulikkal, Hua Chang, Yosef Landesman, John Charlson, Sunila Pradeep. Selinexor, a selective inhibitor of nuclear export (SINE) compound, enhances the anti-tumor activity of Eribulin in leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5314.
Abstract 5096: Characteristics of tumor immune microenvironment in patients carrying comutations of DNA damage response pathways in esophageal cancer
Authors: Hao Chen, Xihua Xia, Junling Zhang, Yanan Chen, Mengli Huang
Journal: Cancer Research (2022)

Abstract Background: Immunotherapy exhibits promising clinical efficacy in treating unresectable esophageal cancer, and several studies have demonstrated that both comutations in DNA damage response (DDR) pathways and tumor immune microenvironment(TIME) could serve as potential biomarkers for immune checkpoint blockade (ICB) treatment. However, the associtation between DDR comutations and TIME remains unclear. Methods: Between April 2020 and September 2020, NGS and TIME analysis of tumor tissue from 22 patients with esophageal cancer were performed by 3D Medicines, Inc., a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. We retrospectively investigated the association between genomic alterations and immune microenvironment features. Among eight DDR pathways, comutations of check point factors(CPF) plus base excision repair(BER), homologous recombination repair(HRR), mismatch repair(MMR) or Fanconi anemia(FA) were defined as "DDR co-mut+", while mutation of CPF or comutations of CPF plus nucleotide excision repair (NER) were defined as “DDR co-mut-”. In addition, the relationship between comutations of DDR pathways and tumor mutational burden (TMB) was also analyzed. Results: 22 patients with esophageal cancer were included for analysis. 16 of 22 patients (72.7%) were male and the median age was 62 years old(range, 52 to 73 years). Based on the definition of DDR co-mut+ and DDR co-mut-, 13 patients were devided into DDR co-mut+ group, and 9 patients belonged to DDR co-mut- group. Gene alterations and TIME analysis revealed that patients with DDR co-mut+ showed a higher abundance of CD56dim natural killer cells in both tumor(p=0.0161) and stroma(p=0.028) compared with DDR co-mut- patients. No differences were observed in the densities of CD8+ T cells, M1-TAMs, and M2-TAMs between DDR co-mut+ and DDR co-mut- patients. TMB analysis displayed slightly higher in DDR co-mut+ group with no significant difference. Conclusions: Patients with DDR co-mut+ showed better infiltration of CD56dim NK cells in tumor and stroma in esophageal cancer. Combination of DDR comutations with TIME features may be a more promising biomarker to guide immunotherapy. Keywords: esophageal cancer; DNA damage response pathway; tumor immune microenvironment; tumor mutational burden Citation Format: Hao Chen, Xihua Xia, Junling Zhang, Yanan Chen, Mengli Huang. Characteristics of tumor immune microenvironment in patients carrying comutations of DNA damage response pathways in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5096.
Abstract 5266: Prognostic role of molecular subclassification based on mutational profiling and tumor-associated neutrophil status in stage III colon cancer
Authors: CY Chan, AWI Lo, KO Lam, HY Ng, CC Chen, ML Lung, JMY Ko
Journal: Cancer Research (2022)

Abstract The traditional prognostic prediction of colon cancer (CC) is based on the tumor-node-metastasis (TNM) system. This, however, is not adequate for clinical decision making due to the existence of inter-patient variations and heterogeneity of underlying molecular pathways. We aim to investigate the prognostic value of molecular subclassification utilizing i) tumor-associated neutrophil (TAN) status by immunohistochemical (IHC) staining; ii) microsatellite instability (MSI) and elevated microsatellite alteration at selected tetranucleotide repeats (EMAST) status by PCR-based microsatellite typing; and iii) next-generation sequencing (NGS) mutational profiling by deep sequencing of a 77-gene oncology panel. In the discovery phase, 130 pairs of archived normal and tumor formalin-fixed paraffin-embedded (FFPE) specimens of stage III CC patients were retrospectively recruited from Queen Mary Hospital. CC patients will be categorized into different molecular subclasses (MSCs) based on the status of TAN/MSI/EMAST/NGS mutational profiling molecular biomarkers. Kaplan-Meier analysis, log rank test, univariate and multivariate Cox proportional hazards regression analysis will be used for estimation of progression-free survival (PFS) and overall survival (OS) between the two groups of CC patients. We expect our data to provide useful information for improved stratification of stage III CC patients into high or low risk of recurrence and survival. Acknowledgement: The Health and Medical Research Fund (07181536) to JMYK. Citation Format: CY Chan, AWI Lo, KO Lam, HY Ng, CC Chen, ML Lung, JMY Ko. Prognostic role of molecular subclassification based on mutational profiling and tumor-associated neutrophil status in stage III colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5266.